Pharmaceutically active 3-(1,2,5,6-tetrahydropyridyl)-pyrrolopyridines

ABSTRACT

Compounds of the formula ##STR1## wherein one of A, B, D and E is N and the remaining three atoms are C; R 1  and R 2  are independently selected from hydrogen and C 1  to C 6  alkyl; and R 3 , R 4 , R 5  and R 6  are independently selected from hydrogen, halogen, hydroxy, C 1  -C 6  alkyl, C 1  -C 8  alkoxy, phenyl-C 1  -C 6  alkoxy, phenoxy --NR 7  R 8  wherein R 7  and R 8  are independently selected from hydrogen, C 1  -C 8  alkyl, C 1  -C 6  alkanoyl and COOR 9  wherein R 9  is hydrogen or C 1  -C 6  alkyl, cyano, COOR 10  wherein R 10  is hydrogen or C 1  -C 6  alkyl, and CONR 11  R 12  where R 10  and R 11  are independently selected from hydrogen and C 1  -C 6  alkyl, and the pharmaceutically acceptable salts thereof. The compounds are useful psychotherapeutics and may be used in treating obesity, depression and disorders wherein aggression is a symptom.

BACKGROUND OF THE INVENTION

The present invention relates to certain pyrrolopyridines, methods ofpreparing such compounds, pharmaceutical compositions comprising suchcompounds, and the use of such compounds in treating obesity,depression, and disorders wherein aggression is a symptom (e.g.,schizophrenia).

U.S. Pat. Nos. 4,232,031 and 4,278,677 refer to tetrahydropyridylindoleshaving antidepressive, antiemetic, antiparkinsonian and neurolepticactivity.

U.S. Pat. Nos. 3,993,764 and 4,196,209 refer to piperidylindoles havingantidepressant, antiemetic and antiparkinsonian activity.

J. Guillaume et al., Eur. J. Med. Chem., 22, 33-43 (1987) refer totetrahydropyridinylindoles having serotoninergic and anti-dopaminergicproperties.

K. Freter, J. Org. Chem., 40, 2525-2529 (1975), refers to the react-ionof cyclic ketones and indoles to prepare 3-cycloalkenylindoles.

G. H. Kennet et al., European Journal of Pharmacology, 141, 429-435(1987), C. Bendotti et al., Life Sciences, 41, 635-642 (1987), M. Carliet al., Psychopharmacology, 94, 359-364 (1988) and P. H. Hutson et al.,Psychopharmacology, 95, 550-552 (1988), refer to the effects of RU 24969(5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole) as a5-hydroxytryptamine agonist, its potential anxiolytic, andantidepressant effects and its effects on feeding.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR2##wherein one of A, B, D and E is N and the remaining three atoms are C;

R¹ and R² are independently selected from hydrogen and C₁ to C₆ alkyl;and R³, R⁴, R⁵ and R⁶ are independently selected from hydrogen, halogen,hydroxy, C₁ -C₆ alkyl, C₁ -C₈ alkoxy, phenyl-C₁ -C₆ alkoxy, phenoxy,--NR⁷ R⁸ wherein R⁷ and R⁸ are independently selected from hydrogen, C₁-C₆ alkyl, C₁ -C₆ alkanoyl, and COOR⁹ wherein R⁹ is hydrogen or C₁ -C₆alkyl, cyano, COOR¹⁰ wherein R¹⁰ is hydrogen or C₁ -C₆ alkyl, and CONR¹¹R¹² where R¹⁰ and R¹¹ are independently selected from hydrogen and C₁-C₆ alkyl, and the pharmaceutically acceptable salts thereof.

The pyrrolo[3,2-b]pyridines of the formula I wherein R¹, R², R⁵ and R⁶are hydrogen, R³ is absent, R⁴ is as defined above, A is N, and B, D andE are C are preferred. Particularly preferred compounds are theforegoing compounds wherein R⁴ is hydrogen, C₁ -C₆ alkoxy (e.g.,methoxy) or hydroxy.

Unless otherwise indicated, the alkyl groups referred to herein, as wellas the alkyl moieties of other groups referred to herein (e.g., alkoxyand alkanoyl), may be linear or branched. They may also be cyclic or belinear or branched and contain cyclic moieties.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the formula I are prepared by reacting a compound ofthe formula ##STR3##wherein A, B, D, E, R², R³, R⁴, R⁵ and R⁶ are asdefined above, with a piperidone monohydrate hydrohalide (preferably,the hydrochloride) in the presence of a base. Suitable bases includesodium orpotassium alkoxides and alkylmagnesium halides. A preferredbase is sodium methoxide. The solvent should be an inert solvent.Suitable solvents include alcohols, dimethylformamide, andtetrahydrofuran. The preferred solvent is methanol. The reaction isconducted at a temperature of about 60° to about 120° C., preferablyabout 65° to about 70° C., most preferably at the reflux temperature ofthe solvent. The pressure is not critical. Generally, the reaction willbe conducted ata pressure of about 0.5 to about 2 atmospheres,preferably at ambient pressure (about 1 atmosphere).

Compounds of the formula I may be converted into the salt of aninorganic or organic acid, preferably into a pharmaceutically acceptablesalt, by reacting substantially stoichiometric amounts of the base andthe acid. Examples of such salts are hydrochlorides, hydrobromides,nitrates, sulfates, phosphates, acetates, oxalates, maleates, fumarates,tartrates, lactates, maleates, malonates, citrates, salicylates,methanesulfonates, benzenesulfonates, toluenesulfonates andnaphthalenesulfonates.

These or other salts of the new compounds, such as, for example,picrates, can also be used to purify the free bases obtained, byconverting the freebase into a salt, separating the salt and ifappropriate recrystallizing itor purifying it by another means, andliberating the base again from the salt.

Compounds of the formula II wherein R², R⁵ and R⁶ are hydrogen, R³ isabsent, R⁴ is as defined above, A is N, and B, Dand E are C are novel.Specific novel compounds are the following:

5-hydroxypyrrolo[3,2-b]pyridine;

5-dimethylaminopyrrolo[3,2-b]pyridine;

5-ethoxypyrrolo[3,2-b]pyridine;

5-propoxypyrrolo[3,2-b]pyridine;

5-butoxypyrrolo[3,2-b]pyridine;

5-isopropoxypyrrolo[3,2-b]pyridine;

5-t-butoxypyrrolo[3,2-b]pyridine;

5-benzyloxypyrrolo[3,2-b]pyridine;

5-cyclopentoxypyrrolo[3,2-b]pyridine; and

5-methylpyrrolo[3,2-b]pyridine.

The novel compounds of the formula II are prepared by reacting acompound of the formula ##STR4##wherein R⁴ is as defined above with2-(4-chlorophenoxy)acetonitrile inthe presence of a strong base in anappropriate polar solvent. (See Makosza, et. al. (Liebigs Ann. Chem.,1988, 203)). Suitable bases include tertiary sodium or potassiumalkoxides. The preferred base is potassium t-butoxide. Suitable solventsinclude tetrahydrofuran, diethyl ether, and dimethylformamide. Thepreferred solvent is tetrahydrofuran. The reaction is conducted at atemperature of about -78° C. to about 25° C., preferably at -10° C. Thepressure is not critical. Generally, the reaction will be conducted at apressure of about 0.5 to about 2 atmospheres, preferably at ambientpressure (about 1 atmosphere). The product of such reaction is purifiedby neutralization of the reaction mixture using a mineral acid,preferably dilute hydrochloric acid, and standard extractive isolationusing ethyl acetate, diethyl ether, or methylene chloride, preferablydiethyl ether. The organic residue from theextraction is reacted under ahydrogen atmosphere in a suitable solvent with a metal catalyst at atemperature between about 0° C. and about 70° C., most preferably atambient temperature (about 20° C.). Suitable solvents include methanol,ethanol, propanol, ethyl acetate, dimethylformamide and acetic acid.Acetic acid is the preferred solvent. Suitable metal catalysts includemixtures of palladium on carbon, palladium oxide, and Raney nickel. Thepreferred catalyst is 10% palladium on carbon. The hydrogen pressure ofthe reaction should be maintained between about 1 atmosphere to about 5atmospheres, preferably at about 3 atmospheres.

The present invention also relates to the use of compounds of theformula Iand their pharmaceutically acceptable salts in the treatmentand preventionof obesity, depression and disorders wherein aggression isa symptom. The effectiveness of such compounds may be measured byadministering the compounds to mice and measuring weight loss. Acompound of the formula I or a pharmaceutically acceptable salt thereofcan be administered alone orin admixture with suitable excipients. Sucha mixture may contain one or more compounds of the formula I orpharmaceutically acceptable salts thereof in an amount of about 0.1 toabout 99.9%. A typical dose for an adult human would range from about 1mg to about 500 mg. The exact dosage of a compound of the formula I or apharmaceutically acceptable salt thereof will depend upon such factorsas the age, weight and condition of the patient and the severity ofdisease. In general, however, a therapeutically effective dose of acompound of the formula I or a pharmaceutically acceptable salt thereofwill range from about 0.1 to about 20 mg/kg body weight of the subjectto be treated per day, preferably about 2 to about 10 mg/kg per day,taken in up to 4 divided doses.

Possible pharmaceutical formulations include all those formulations withwhich the expert is familiar, such as, for example, suppositories,powders, granules, tablets, capsules, dragees, suspensions and solutionsfor oral administration, injectable solutions and transdermal systems.Solid, semi-solid or liquid excipients or diluents can be used toprepare pharmaceutical formulations. These agents include binders,lubricants, emulsifiers and the like. Examples of such agents are:starch, such as potato starch and cereal starch, sugar, such as lactose,sucrose, glucose,mannitol and sorbitol, cellulose, such as crystallinecellulose, methylcellulose, calcium carboxymethylcellulose, sodiumcarboxymethyl cellulose and hydroxypropylcellulose, inorganic materials,such as potassium phosphate, calcium sulfate, calcium carbonate, talc,gelatin, gum arabic, polyvinylpyrrolidone, magnesium stearate, cacaobutter, surface-active substances, such as fatty acid glycerides, fattyacid sorbitan esters, fatty acid esters of sucrose and polyglycerol, andothers.

The following Examples illustrate the preparation of the compounds ofthe present invention. Melting points are uncorrected. NMR data arereported in parts per million (δ) and are referenced to the deuteriumlock signal from the sample solvent. The starting materialspyrrolo[3,2-b]pyridine (V. A. Azimov et al., Khim. Geterotsikl Soedin.,10, 1425 (1977)), pyrrolo[3,2-c]pyridine (J. R. Dormoy, et al. Fr.DemandeFR 2,564,836 (Nov. 29, 1985)), pyrrolo[2,3-c]pyridine (A. A.Prokopov et al. Khim. Geterotsikl Soedin., 8, 1135 (1977)),pyrrolo[2,3-b]pyridine (Aldrich Chemical Co.),5-methoxypyrrolo[3,2-b]pyridine (M. Makoska, et al., Liebigs Ann. Chem.,203 (1988)), and 4-methyl-5-nitro-1H-pyridine-2-one (H. E. Baumgarten,et al. JACS, 74, 3828 (1952)) are commercially available or may beprepared according to published methods.

EXAMPLE 1 A. General procedure for the synthesis of3-(1,2,5,6-tetrahydropyridyl)pyrrolopyridines; Compounds 1a-1m, 2, 3a,3b, 3c and 4

To a stirred solution of Na (2.53 g, 110 mmol, 11 eq) in absolutemethanol (50 ml) at room temperature was added the appropriatepyrrolopyridine (10.00 mmol) and piperidone monohydrate hydrochloride(4.60 g, 30.0 mmol, 3.0 eq). The resultant mixture was then heated atreflux under nitrogen for 2-24 hours depending on the substrate. Theresultant reaction mixture was cooled, and concentrated hydrochloricacid (37%, 9.0 ml, 110 mmol) wasadded dropwise with vigorous stirring.The resultant mixture was then evaporated under reduced pressure, andthe residual slurry placed in water(50 ml). This aqueous mixture wasextracted with ethyl acetate (5×50 ml), and these extracts werecombined, dried (Na₂ SO₄), and evaporated under reduced pressure. Theresidue was either triturated directly or column chromatographed usingsilica gel (approximately 100 g) and elution with the appropriatesolvent system yielding the desired3-(1,2,5,6-tetrahydropyridyl)pyrrolopyridine, one of Compounds 1a-1m orcompound 2, 3a, 3b, 3c or 4.

B. 3-(1,2,5,6-Tetrahydropyridyl)pyrrolo[3,2-b]pyridine (Compound 1a)

The reaction time was 4 hours. Flash chromatography of the extractionresidue using silica gel (approximately 200 g) and elution with 5%triethylamine in methanol yielded Compound la (44%) as a pale yellowsolid: mp, 198°-200° C.; IR (KBr) 3220, 3100-2740, 1650, 1615, 1550,1500, 1460, 1430, 1260, 1040 cm⁻¹ ; ¹ H NMR (DMSO-d₆)δ8.33 (dd, J=4.7and 1.2 Hz, 1H), 7.72 (dd, J=8.3 and 0.8 Hz, 1H), 7.55 (s, 1H), 7.11 (brm, 1H), 7.09 (dd, J=8.3 and 4.7 Hz, 1H), 3.39 (d, J=2.6 Hz, 2H), 2.92(t, J=5.8 Hz, 2H), 2.36 (br m, 2H); ¹³ C NMR (DMSO-d₆)δ143.6, 142.0,129.5, 128.2, 125.0, 121.6, 118.4, 116.3, 116.0 44 8, 42.8, 27.2; LRMS(m/z, relative intensity) 200 (30), 199 (M+, 100), 198 (92), 170 (75),169 (39), 155 (15), 131 (35); HRMS calculated for C₁₂ H₁₃ N₃ :199.1110,found: 199.1096.

5-Methoxy-3-(1,2,5,6-tetrahydropyridyl)pyrrolo[3,2-b]pyridine (Compound1b)

The reaction time was 6 hours. Flash chromatography of the extractionresidue using silica gel (approximately 100 g) and elution with 10%triethylamine in methanol, followed by crystallization of the recoveredoil (R_(f) =0.15 in 10% triethylamine in methanol) in 1:1 methylenechloride/ethyl ether afforded compound 1b (39%) as pale yellow solid:mp, 208-210° C.; IR (KBr) 3300, 3120-2730, 1650, 1620, 1580, 1490, 1435,1410, 1250 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.66 (br s,1H), 7.50 (d, J=9.0 Hz,1H), 7.25 (br m, 1H), 7.20 (s, 1H), 6.58 (d, J=9.0 Hz, 1H), 3.98 (s,3H), 3.63-3.60 (m, 2H), 3.14 (t, J=5.7 Hz, 2H), 2.47-2.43 (m, 2H), 1.78(br s, 1H); ¹³ C NMR (proton coupled, CDCl₃) δ 160.0 (s), 140.1 (s),128.5 (s), 125.4 (s), 122.7 (d),122.0 (d) 121.8 (d), 117.0 (s), 105.5(d), 53.2 (q), 45.5 (t), 43.4 (t), 27.4 (t); LRMS (m/z relativeintensity) 230 (27), 229 (M+, 100), 228 (38),214 (49), 212 (22), 199(22), 197 (42), 187 (26), 186 (33), 185 (32), 171 (41); HRMS calculatedfor C₁₃ H₁₅ N₃ O:229.1215, found: 229.1185.

D. 5-Ethoxy-3-(1,2,5,6-tetrahydropyridyl)pyrrolo-[3,2-b]pyridine (1c)

The reaction time was 5 hours. Flash chromatography using silica gel andelution with 10% triethylamine in methanol yielded Compound 1c (48%) asa yellow powder mp, 186°-189° C.; IR (KBr) 3430-2810, 1645, 1610, 1575,1480, 1475,1435, 1410, 1275, 1230 cm⁻¹ ; 1H NMR (DMSO-d₆) δ 11.2(br s,1H), 7.68 (d, J=8.8 Hz, 1H), 7.45 (s,1H), 7.06 (br m, 1H), 6.54 (d, J=8.7 Hz, 1H), 4.4 (br s, 1H), 4.33 (q,J =7.0 Hz, 1H), 3.47 (br m, 2H),2.99 (br m, 2H), 2.41 (br m, 2H) 1.35 (t, J =7.0 Hz, 6H); ¹³ C NMR(DMSO-d₆) δ 158.3, 139.4, 128.6, 125.4, 124.2, 122.5, 119.5, 115.1,104.6, 60.5, 44.4, 42.4, 26.8, 14.7; LRMS (m/z, relative intensity) 244(M+, 100), 214 (81), 197 (94), 185 (33), 171 (49); HRMS calculated forC₁₄ H₁₇ N₃ O: 243.1372,found: 243.1367.

E. 5-Propoxy-3-(1,2,5,6-tetrahydropyridy)pyrrolo-[3,2-b]pyridine (1d)

The reaction time was 6 hours. Flash chromatography using silica gel andelution with 10% triethylamine in methanol yielded Compound 1d (78%) asa yellow foam; mp, 170°-173° C.; IR (KBr) 1640, 1620, 1575, 1470, 1455,1410, 1270, 1235 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 11.1 (br s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.42 (s, 1H), 7.06 (br s1H), 6.55 (d, J =8.7 Hz, 1H), 4 24(q, J =6.6 Hz, 1H), 3.41 (br m, 2H), 2.93 (t, J =5.6 HZ, 2H), 2.36 (brm, 2H), 1.82-1.71 (m, 2H), 0.98 (t, J =7.4 Hz, 6H); ¹³ C NMR (DMSO-d₆) δ158.5, 139.5, 128.5, 125.4, 123.9, 122.4, 120.8, 115.4, 104.6, 66.4,45.0, 42.9, 27.3, 22.0, 10.7; LRMS (m/z, relative intensity), 258 (20),257 (M+, 95), 215 (20), 214 (91), 198 (26), 197 (100), 185 (38), 172(20), 171 (53), 169 (28); HRMS calculated for C 257.1528, found:257.1536.

F. 5-Isopropoxy-3-(1,2,5,6-tetrahydropyridyl)pyrrolo-[3,2-b]pyridine(Compound 1e)

The reaction time was 6 hours. Flash chromatography of the extractionresidue using silica gel (approximately 100 g) and elution with 5%triethylamine in methanol yielded Compound 1e (60%) as a pale yellowfoam;IR (KBr) 3400-2800 (br), 1650, 1615, 1580 1470, 1415, 1385, 1370cm⁻¹ ; 1H NMR (DMSO-d₆) δ 7.64 (d, J=8.5 Hz, 1H) (br m, 1H), 7.03 (br m,1H), 6.47 (d, J=8.6 Hz, 1H), 5.25 (sept, J=6.3 Hz, 1H), 3.40 (br m,2H),3.04 (br s, 1H), 2.93 (t, J=5.2 Hz, 2H), 2.36 (br m, 2H), 1.31 (d, J=6.3Hz, 6H); ¹³ C NMR (DMSO-d₆) δ 157.8, 139.5, 128.6, 125.2, 124.0, 122.4,120.4, 115.3, 105.1, 66.7, 44.9, 42.8, 27.2, 22.0; LRMS (m/z, relativeintensity) 258 (10), 257 (M+, 69), 214 (79), 197 (100), 185 (22), 172(22); HRMS calculated for C₁₅ H₁₉ N₃ O257.1528, found: 257.1535.

G. 5-Butoxy-3-(1,2,5,6-tetrahydropyridyl)pyrrolo-[3,2-b]pyridine (1f)

The reaction time was 19 hours. Flash chromatography using silica geland elution with 5% triethylamine in methanol yielded a yellow solid.Cold methanol was added to this solid to prepare a slurry. Theundissolved solid was filtered to yield Compound 1f (29%) as a yellowpowder: mp, 158°-160° C.; IR (KBr) 2950-2620, 1640, 1620, 1575, 1500,1470, 1450, 1440, 1410, 1380 cm¹ ; 1H NMR (DMSO-d₆) δ 11.1(br s, 1H),7.66 (d, J=8.7 Hz, 1H), 7.42 (s, 1H), 7.07 (br m, 1H), 6.53 (d,J=8.7 Hz,1H), 4.29 (t, J=6.6 Hz, 1H), 3.41 (br m, 2H), 2.93 (br t, 2H), 2.36 (brm, 2H), 1.78-1.68 (m, 2H), 1.50-1.38 (m, 2H), 0.94 (t, J=7.4 Hz, 6 H);¹³ C NMR (DMSO-d₆) δ 158.4 139.5, 128 5, 125.4, 123.9, 122.4, 120.8,115.4, 104.6, 64.5, 45.0, 42.9, 30.7, 27.2, 19.0, 13.8; LRMS (m/z,relative intensity) 272 (54), 271 (98, M+), 270 (23), 243(13), 228 (11),215 (28), 214 (100), 212 (30), 198 (35), 197 (97), 187 (21), 185 (43),172 (28), 171 (62), 169 (34); Anal. calculated for C₁₆ H₂₁ N₃ O: C,70.82; H, 7.80; N, 15.48; found: C, 70.17 H, 7.86; N, 15.26.

H. 5-t-Butoxy-3-(1,2,5,6-tetrahydropyridyl)pyrrolo[3,2-b]pyridine (1g)

The reaction time was 18 hours. Flash chromatography using silica geland elution with 5% triethylamine in methanol yielded Compound 1g (48%)as a yellow foam: IR (KBr) 1650, 1610, 1575, 1480, 1450, 1410, 1180 cm⁻¹;1H NMR (DMSO)d₆ δ 11.5 (br s, 1H), 7.67 (d, J =8.8 Hz, 1H), 7.58(s,1H), 6.99 (br s, 1H), 6.48 (d, J =8.7 Hz, 1H), 3.73 (br m, 2H), 3.28 (brt, 2H) 2.74 (br m, 2H) 1.58 (s, 9H); LRMS (m/z, relative intensity) 271(M+, 16), 215 (71), 214 (86), 198 (43), 197 (75), 186 (25), 185 (38),173 (32), 172 (100), 171 (25), 169 (20); HRMS calculated for C₁₆ H₂₁ N₃O: 271.1685, found: 271.1681.

I. 5-Benzoxy-3-(1,2,5,6-tetrahydropyridyl)pyrrolo [3,2-b]pyridine (1h)

The reaction time was 6 hours. Flash chromatography using silica gel andelution with 5% triethylamine in methanol yielded Compound 1h (40%) as ayellow solid which was converted to its maleic acid salt: mp, 185°-187°C.; IR (KBr) 1645, 1610, 1580, 1480, 1465, 1415, 1365, 1275 cm⁻¹ ; 1HNMR (DMSO-d₆) δ 11.4 (br s, 1H), 8.9 (br s, 2H), 7.76 (d, J =8.8 Hz,1H), 7.62 (d, J =2.9 Hz, 1H), 7.49-7.47 (m, 2H), 7.40-7.28 (m, 3H), 7.05(br s, 1H), 6.68 (d, J =8.7 Hz, 1H), 6.05(s, 2H), 5.39 (s, 2H), 3.81 (brm, 2H), 3.36 (t, J =6.0 Hz, 2H), 2.71 (br m, 2H); ¹³ C NMR (DMSO-d₆) δ167.3, 158.3, 139.1, 138.2, 136.1, 128.5, 128.3, 127.8, 127.5, 125.6,125.4, 123.0, 113.2, 112.9, 105.2, 66.7, 41.7, 40.4, 23.1; LRMS (m/z,relative intensity) 305 (M+, 4),264 (3), 228 (8), 214 (96), 197 (100),91 (75), 72 (28); HRMS calculated for C₁₉ H₁₉ N₃ O: 305.1528, found:305.1542.

J. 5-Cyclopentoxy-3-(1,2,5,6-tetrahydrophridyl)-pyrrolo[3,2-b]pyridine(1i)

The reaction time was 24 hours. Flash chromatography using silica geland elution with 5% triethylamine in methanol yielded Compound 1i (78%)as a yellow solid which was converted to its maleic acid salt: mp,210°-211° C.; ¹ H NMR (DMSO-d₆) δ 11.3 (br s, 1H), 8.8 (br s, 2H), 7.70(d, J =8.8 Hz, 1H), 7.60 (d, J =2.9 Hz, 1H), 7.10 (br m, 1H), 6.54 (d, J=8.8 Hz, 1H), 6.05 (s, 2H), 5.40-5.35 (m, 1H),3.82 (br m, 2H), 3.37 (t,J =6.0 Hz, 2H), 2.73 (br m, 2H), 2.02-1.93 (m, 2H), 1.80-1.57 (m, 6H);¹³ C NMR (DMSO-d₆) δ 167.3, 158.4,139.4, 136.1, 128.8, 125.3, 125.2,122.8, 113.2, 112.6, 105.6, 76.8, 41.7, 32.6, 23.8, 23.1; LRMS (m/z,relative intensity) 283 (26), 215 (24), 214 (100), 198 (38), 197 (83),185 (28), 173 (23), 172 (71), 171 (26), 169 (23), 121 (30), 72 (50);HRMS calculated for C₁₇ H₂₁ N₃ O: 283.1684, found: 283.1684.

K. 5-Hydroxy-3-(1,2,5,6-tetrahydropyridyl)pyrrolo[3,2-b]pyridine(Compound 1j)

The reaction time was 6 hours. Flash chromatography of the extractionresidue using silica gel (approximately 100 g) and elution with 10%triethylamine in methanol yielded a white foam. This foam was trituratedin 5% methanol/ethyl acetate to yield Compound 1j (65%) as an off-whitesolid: mp, decomposes 248.0° C.; IR (KBr) 3280, 1620, 1450, 1415, 1385,1340 cm⁻¹ ; 1H NMR (DMSO-d₆) δ 11.1 (br s, 1H), 7.56(d, J=9.3 Hz, 1H),7.23 (s, 1H), 6.39 (br m, 1H), 6.15 (d, J=8.9 Hz, 1H), 3.33 (br m, 2H),2.88 (t, J=5.6 Hz, 2H), 2.26 (br m, 2H); ¹³ C NMR (DMSO-d₆) δ 161.0,132.3, 127.7, 126.2, 122.6, 121.8, 121.2, 112.9, 109.4, 44.7, 42.8,27.8; LRMS (m/z, relative intensity) 216 (27), 215 (M+, 100), 214 (25),198 (30), 197 (52), 186 (36), 185 (49), 173 (29),172 (75), 171 (34), 147(21); HRMS calculated for C₁₂ H₁₃ N₃O: 215.1058, found: 215.1032.

L. 5-Chloro-3-(1,2,5,6-tetrahydropyridyl)pyrrolo[3,2-b]pyridine(Compound 1k)

The reaction time was 6 hours. Flash chromatography of the extractionresidue using silica gel (approximately 100 g) and elution with 10%triethylamine in methanol, followed by crystallization of the recoveredoil using ethyl acetate yielded Compound 1k (38%) as a pale yellowsolid: mp, 178°-180° C.; IR (KBr) 3400, 3120-2600, 1650, 1620, 1555,1490, 1410, 1425 cm⁻¹ ; 1H NMR (DMSO-d₆) δ 11.54 (brs, 1H), 7.81 (d,J=8.6 Hz, 1H), 7.66 (s, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.95 (br m, 1H),3.39 (br m, 2H), 3.25 (br s, 1H), 2.92 (t, J=5.6 Hz, 2H), 2.36(br m,2H); LRMS (m/z relative intensity) 235 (21), 234 (17), 233 (M+, 74),232(33 ), 218 (25), 217 (20), 215 (27), 205 (32), 204 (36), 203 (41), 192(43), 191 (47), 190 (100), 167 (21), 165 (36), 98 (28); HRMS calculatedfor C₁₂ H₁₂ N₃ Cl:233.0720, found: 233.0681.

M. 5-Dimethylamino-3-(1,2,5,6-tetrahydropyridyl)-pyrrolo-[3,2-b]pyridine(Compound 1l)

The reaction time was 6 hours. Trituration of the extraction residueusing ethyl acetate yielded Compound 11 (17%) as a pale yellow powder:mp, decomposes at 120° C.; IR (KBr) 1610, 1580, 1490, 1405, 1365 cm⁻¹ ;¹ H NMR (DMSO-d₆) δ 7.53 (d, J=8.9 Hz, 1H), 7.31 (s, 1H), 7.13 (br m,1H), 6.54 (d, J=8.9 Hz, 1H), 4.02 (br m, 2H), 3.44 (br m, 2H), 3.01 (s,6H), 2.38 (br m, 2H); LRMS (m/z relative intensity) 243 (20), 242 (M+,100), 227 (32), 214 (20), 210 (24), 209 (23), 196 (22), 184 (24); HRMScalculated for C₁₄ H₁₈ N₄ : 242.1532, found: 242.1536.

N. 5-Methyl-3-(1,2,5,6-tetrahydropyridyl)pyrrolo[3,2-b]pyridine(Compound 1m)

The reaction time was 23 hours. Flash chromatography using silica geland elution with 5% triethylamine in methanol yielded Compound 1m (49%)as a yellow glass which was converted to its maleic acid salt: mp,158°-159° C. with decomposition; IR (KBr) 1640, 1610, 1570, 1510, 1415,1385, 1370 cm⁻¹ ; 1H NMR (DMSO-d₆) δ 11.3 (br s, 1H), 8.8 (br s, 2H),7.69-7.67 (m, 2H), 7.23 (br m, 1H), 7.03 (d, J =8.3 Hz, 1H), 6.04 (s,2H), 3.82 (br m, 2H), 3.36 (br m, 2H), 2.73 (br m, 2H), 2.56 (s, 3H);LRMS (m/z, relative intensity) 214 (12), 213 (M+, 100),212 (39), 198(26), 185 (28), 184 (32 ), 183 (36), 171 (32), 170 (56), 72 (34); HRMScalculated for C₁₃ H₁₅ N₃ O: 213.1258, found: 213.1268.

O. 3-(1,2,5,6-Tetrahydropyridyl)pyrrolo[3,2-c]pyridine (Compound 2)

The reaction time was 2 hours. Flash chromatography of the extractionresidue using silica gel (approximately 200 g) and elution with 5%triethylamine in methanol yielded Compound 2 (8%) as a pale yellowsolid: mp, 200°-202° C.; IR (KBr) 3400, 3240-2740, 1640, 1575, 1535,1470, 1445, 1350 cm⁻¹ ; 1H NMR (DMSO-d₆) δ 11.7 (br s, 1H), 9.17 (s,1H), 8.22 (d, J=8.5 Hz, 1H), 7.45 (s, 1H), 7.36 (d, J=8.5Hz, 1H), 6.29(br s, 1H), 3.42 (br m, 2H), 2.95 (br m, 2H), 2.40 (br m, 2H); ¹³ C NMR(DMSO-d₆) δ 142.8, 140.3, 140.1, 129.2, 123.1, 121.9, 121.3, 116.7,106.9, 44.7, 42.6, 27.9; LRMS (m/z, relative intensity) 200 (34), 199(M+, 100), 198 (84), 171 (29), 170 (74), 169 (36), 155 (20), 143 (13),131 (42), 119 (19); HRMS calculated for C₁₂H₁₃ N₃ : 199.1110, found:199.1071.

P. 3-(1,2,5,6-Tetrahydropyridyl)pyrrolo[2,3-c]pyrrolo (Compound 3a)

The reaction time was 4 hours. Flash chromatography of the extractionresidue using silica gel (approximately 200 g) and elution with 5%triethylamine in methanol yielded compound 3a (28%) as a pale yellowsolid: mp, 208°-210° C.; IR (KBr) 3220, 3120-2740, 1640, 1500, 1460,1430, 1260, 1140 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 8.71 (d, J=1.7 Hz, 1H), 8.09(d, J=5.6 Hz, 1H), 7.74 (dd, J=1.6 and 5.6 Hz, 1H), 7.59 (s, 1H), 6.19(br m, 1H), 3.39 (d, J=3.0 Hz, 2H), 3.28 (br s, 1H), 2.92 (t, J=5.8 Hz,2H), 2.38 (br m, 2H); ¹³ C NMR (DMSO-d₆) δ 138.1, 134.8, 134.0, 129.3,128.6, 126.0, 120.6, 116.2, 114.6, 44.7, 42.7, 27.9; LRMS (m/z, relativeintensity) 200 (14), 199 (M+100), 198 (76), 170 (49), 169 (25), 156(10), 142 (10), 131 (23); HRMS calculated for C₁₂ H₁₃ N₃ : 199.1110,found: 199.1100.

Q. 5-Methoxy-3-(1,2,5,6-tetrahydropyridyl)pyrrolo-[2,3-c]pyridine(Compound3b)

The reaction time was 4 hours. Trituration of the extraction residuewith methylene chloride afforded a pale yellow solid. This solid wasdissolved with methanol/methylene chloride, and maleic acid (1.05 eq)was added to this solution. Addition of ethyl ether triturated themaleate salt of Compound 3b (40%) as a pale yellow powder: mp,decomposes 170° C.; IR (KBr) 3100-2600, 1720, 1630, 1480, 1370, 1230cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 11 57 (br s, 1H), 8.87 (br s, 2H), 8.40 (s,1H), 7.75 (s, 1H), 7.14 (s, 1H) 6.14 (br m, 1H), 6.09 (s, 2H), 3.85 (s,3H), 3.78 (br m, 2H), 3.36 (br t, 2H), 2.71 (br m, 2H); ¹³ C NMR(DMSO-d₆) δ 167.3, 157.9, 135.4, 132.9, 131.5, 130.6, 129.8, 129.3,113.3, 112.4, 97.3, 53.6, 41.6, 23.9; LRMS (m/z, relative intensity) 230(19), 229 (M+, 100), 228 (77), 212 (24), 201 (63), 200 (65), 199 (27),185 (46), 150 (20), 114 (33), 99 (54), 87 (21), 57 (78); HRMS calculatedfor C₁₃ H₁₅ N₃ O: 229.1215, found: 229.1232.

R. 5-Chloro-3-(1,2,5,6-tetrahydropyridyl)pyrrolo[2,3-c]pyridine(Compound 3c)

The reaction time was 9 hours. Trituration of the extraction residuewith ethyl acetate afforded Compound 3c (54%) as a pale yellow powder:mp, 230°-233° C.; IR (KBr) 3420, 3240, 1610, 1545, 1450 cm⁻¹ ; ¹ H NMR(DMSO-d₆) δ 8.52 (s, 1H), 7.77 (s, 1H), 7.71 (s, 1H), 6.16 (br m, 1H),3.38 (br m, 2H), 3.20 (br s, 1H), 2.91(t, J=5.3 Hz, 2H), 2.35 (br m,2H); ¹³ C NMR (DMSO-d₆) δ 139.4, 134.0, 133.4, 131.8, 128.7, 128.6,121.8, 116.3, 113.7, 44.8, 42.7,28.1; LMRS (m/z, relative intensity) 235(48), 234 (53), 233 (M+, 100), 232(94), 206 (21), 204 (53), 169 (27),165 (24); HRMS calculated for C₁₂ H₁₂ N₃ Cl:233.0720, found: 233.0671.

S. 3-(1,2,5,6-Tetrahydropyridyl)pyrrolo[2,3-b]pyridine (Compound 4)

The reaction time was 4 hours. Trituration of the extraction residuewith ethyl acetate afforded Compound 4 (63%) as a pale yellow solid: mp,199.0°-202.0° C.; IR (KBr) 3280, 3100-2740, 1650, 1595, 1570, 1520,1495, 1450, 1415, 1330, 1240 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 11.65 (br s,1H), 8.20 (d, J=6.7 Hz, 1H), 7.47 (s,1H), 7.08-7.03 (m, 2H), 6.18 (br m,1H), 3.39-3.34 (br m, 2H), 2.92 (br m, 2H), 2.37 (br m, 2H); LRMS (m/z,relative intensity) 200 (21), 199 (M+, 100), 198 (77), 171 (22), 170(87), 169 (36), 155 (22), 143 (22), 142 (23), 131 (67), 80 (23); HRMScalculated for C₁₂ H₁₃ N₃ : 199.1110, found: 199.1059.

EXAMPLE 2 (6-Chloro-3-nitro-2-pyridyl)acetonitrile (Compound 5a) and(6-chloro-3-nitro-4-pyridyl)acetonitrile (Compound 6)

To a stirred solution of potassium tert-butoxide (24.69 g, 220 mmol, 2.2eq) in anhydrous tetrahydro furan (150 ml) at -50° C. under nitrogen, asolution of 2-chloro-5-nitropyridine (15.85 g, 100 mmol) and(4-chlorophenoxy)acetonitrile (E. Grochowski et al., Bull. Acad. Pol.Sci.Ser. Sci. Chim. 11, 443 (1963)) (18.44 g, 110 mmol, 1.1 eq) inanhydrous tetrahydrofuran (150 ml) was added dropwise at such a ratethat the reaction temperature was maintained at -40° to -50° C. withcooling in a dry ice/acetone bath. The resultant purple colored reactionmixture was then stirred at -78° C. under nitrogen for 1 hour, at whichtime glacial acetic acid (20 ml, 0.35 mol, 3.5 eq) was added to thereaction, and the mixture was allowed to warm to room temperature. Asolution of 5% HCl (100 ml) was added to the reaction mixture and thisaqueous mixture was extracted with ethyl ether (100 ml) and then withmethylene chloride (2×100 ml). The extracts were combined, dried(MgSO₄), and passed through a silica gel filter (approximately 150g)followed by methylene chloride (1200 ml). This filtrate was evaporatedunder reduced pressure, and the residual oil was chromatographed usingsilica gel (approximately 300 g) and eluted with 25% hexanes inmethylene chloride to afford an oil (R_(f) =0.52 in methylene chloride)which was triturated in cold anhydrous ether to afford Compound 5a (1.37g, 7%) as awhite crystalline solid: mp, 121.5°-123.5° C.; IR (KBr)3070,2240, 1600, 1560, 1525, 1430, 1390, 1370, 1345, 1185 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 8.45 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 4.38 (s, 2H);¹³ C NMR (CDCl₃) δ 155.5, 146.8, 143.2, 136.2, 125.5, 114.4, 26.7; LRMS(m/z, relative intensity) 199 (10), 198 (12), 197 (M+, 30), 170 (23),151 (39), 126 (75), 125 (20), 124 (100), 116(29), 115 (54), 112 (23), 99(49), 88 (24), 79 (75); Anal. calc'd for C₇ H₄ ClN₃ O₂ : C, 42.55; H,2.04; N, 21.27; found: C,42.52; H, 1.89; N, 20.95.

Further elution yielded another oil (R_(f) =0.48 in methylene chloride)which was triturated in cold anhydrous ethyl ether to afford Compound 6(1.87 g, 9%) as a white crystalline solid: mp, 87°-89° C.; IR (KBr)3080, 2240, 1600, 1545, 1520, 1450, 1390, 1340, 1135 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 9.17 (s, 1H), 7.76 (s, 1H), 4.27 (s, 2H); ¹³ C NMR (CDCl₃) δ157.4, 147 3, 137.7, 125.5, 14.4, 22.5; LRMS (m/z, relative intensity)199 (39), 197 (M+, 100), 182 (28), 180 (70), 153 (29), 152 (31), 51(67), 127 (29), 126 (61), 125 (35), 124 (64), 116 (32), 115 (47), 114(35), 99 (33), 98 (21), 97 (46); Anal. calc'd for C₇ H₄ ClN₃ O₂ : C,42.55; H, 2.04; N, 1.27,found: C, 42.35; H, 1.95; N, 20.94.

EXAMPLE 3 (6-Chloro-3-nitro-2-pyridyl)acetonitrile (Compound 5a)

To a stirred solution of NaH (60%, 1.84 g, 46 mmol, 2.3 eq) and ethylcyanoacetate (4.90 ml, 46 mmol, 2.3 eq) in anhydrous tetrahydrofuran (30ml) at 0° C., a solution of 2,6-dichloro-3-nitropyridine (3.86 g, 20.0mmol) in anhydrous tetrahydrofuran (20 ml) was added dropwise. Theresulting reaction mixture was stirred at 0° C. under nitrogen for 90minutes, during which time the reaction slowly changed color from yellowto deep red. A solution of 5% HCl (40 ml) was then added to the reactionmixture, and this aqueous mixture was extracted with ether (40 ml) andthen methylene chloride (40 ml). The extracts were combined,dried(MgSO₄), and evaporated under reduced pressure. The residual oilwas passed through a silica gel filter (approximately 200 g) followed by10% ethyl acetate/hexanes (1.5 L), 2:1 hexanes/ethyl acetate (2 L), and1:1 ethyl acetate/hexanes (1 L). The latter 3 L were evaporated underreduced pressure to yield a clear, pale yellow oil (7.2 g). This oil wasplaced inan aqueous solution of 2M HI (30 ml), and this mixture washeated at refluxfor 5 hours. The resultant reaction mixture wasextracted with methylene chloride (3×30 ml), and these extracts werecombined, dried (MgSO₄), and passed through a silica gel filter(approximately 150 g)followed by methylene chloride (1 L). This filtratewas evaporated under reduced pressure, and the residual solid wasstirred in cold anhydrous ethyl ether. The undissolved solid wasfiltered to afford Compound 5a (1.16 g, 5.87 mmol, 29% overall) as anoff-white, crystalline solid: mp, 119°-121° C. The physical and spectralproperties of this solid were identical to the physical and spectralproperties of the Compound 5a described in Example 2.

EXAMPLE 4 6-Benzyloxy-3-nitro-2-pyridyl)acetonitrile (Compound 5b)

To a stirred solution of potassium tert-butoxide (12.34 g, 110 mmol, 2.2eq) in anhydrous dimethylformamide (100 mL) at -10° C. was addeddropwise a solution of (4-chlorophenoxy)acetonitrile (9.22 g, 55 mmol,1.1eq) and 2-benzyloxy-5-nitropyridine (H. L. Friedman et al., J. Am.Chem. Soc., 69, 1204 (1947)) (11.51 g, 50.0 mmol) in anhydrousdimethylformamide(50 mL). The resultant deep purple-colored solution wasstirred at -10° C. under nitrogen for 1 hour. Then an aqueous 5% HClsolution 85 mL) added dropwise to the reaction solution at 0° C., andthe precipitated solid was filtered and dried to yield a brown solid(13.4 g).This solid was dissolved in methylene chloride (50 mL), andthis solution was passed through a silica gel filter (approximately 500g) followed by an elution of methylene chloride (4 L). This filtrate wasevaporated underreduced pressure, and the residual oil crystallized inethyl ether/hexanes (1:1) to yield Compound 5b (11.15 g, 41.4 mmol, 83%)as an off-white solid: mp, 63.0°-67.0° C.; IR (KBr) 2260, 1590, 1515,1470, 1455, 1450, 1420, 1350, 1295 cm³¹ ; ¹ H NMR (CDCl₃) δ8.41 (d,J=8.8 Hz, 1H), 7.56-7.31 (m, 5H), 6.90 (d, J=8.8 Hz, 1H), 5.60 (s,2H),4.43 (s, 2H); LRMS (m/z, relative intensity) 270 (12), 269 (M+, 55), 107(29), 92 (39), 91 (100), 65 (55). Anal. calcd. for C₁₄ H₁₁ N₃ O₃ : C,2.45; H, 4.12; N, 15.61; found: C, 62.19; H, 4.05; N,5.55.

EXAMPLE 5 (6-Dimethylamino- 3-nitro-2-pyridyl)acetonitrile (Compound 5c)

To a stirred solution of potassium tert-butoxide (12.34 g, 110 mmol, 2.2eq) in anhydrous dimethylformamide (100 mL) at -10° C. was addeddropwise a solution of (4-chlorophenoxy)acetonitrile (9.22 g, 55 mmol,1.1eq) and 2-dimethylamino-5-nitropyridine (Pfaltz and Bauer, Inc., 8.36g, 50.0 mmol) in anhydrous dimethylformamide (50 mL). The resultant deeppurple-colored solution was stirred at -10° C. under nitrogen for 1hour.Then an aqueous 5% HCL solution (85 mL) added dropwise to the reactionsolution at 0° C., and the precipitated solid was filteredand dried toyield Compound 5c (8.60 g, 41.7 mmol, 83%) as a yellow solid: mp,156.0-158.0° C.; IR (KBr) 2240, 1600, 1580, 1530, 1485, 1420, 1385, 1335cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.25 (d, J=9.0 Hz, 1H), 6.45 (d, J=9.6 Hz, 1H),4.38 (s, 2H), 3.25 (br s, 6H); LRMS (m/z,relative intensity) 207 (13),206 (M+, 100), 191 (54), 189 (26), 177 (88), 160 (35), 159 (22), 145(94), 134 (30), 131 (24), 119 (29), 118 (59), 93 (27). Anal. calcd. forC₉ H₁₀ N₄ O₂ : C, 52,42; H, 4.89; N, 27.17; found: C, 52.19; H, 4.93; N,26.93.

EXAMPLE 6 5-Chloropyrrolo[3,2-b]pyridine (Compound 7a)

A mixture of 500 mg Raney nickel (washed thoroughly with absoluteethanol),Compound 5 (1.70 g, 8.60 mmol), and 1:1 absolute ethanol/aceticacid (30 ml) was shaken under a hydrogen atmosphere (3 atm) for 2 hours.The reaction mixture was filtered, and the filtrate was evaporated underreduced pressure. The residual oil was placed in a saturated solution ofsodium bicarbonate (10 ml), and this aqueous mixture was extracted withmethylene chloride (3×25 ml). These extracts were combined, dried(MgSO₄), and evaporated under reduced pressure. The residual solid wasstirred in cold anhydrous ethyl ether, and the undissolved solid wasfiltered to yield Compound 7a (0.65 g, 4.26 mmol, 50%) as a white solid:mp, 200°-203° C.; IR (KBr) 3140-2700, 1620, 1555, 1500, 1460, 1450,1415, 1335 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.92 (br, s 1H), 7.67 (d, J=8.0 Hz,1H), 7.48 (t, J=2.9 Hz, 1H), 7.11 (d, J=7.9Hz, 1H), 6.67-6.65 (m, 1H);LRMS m/z, relative intensity) 154 (46), 153 (17), 152 (M+, 100), 117(81), 90 (17), 63 (15); HRMS calculated for C₇ H₅ ClN₂ :152.0141, found:152.0131 (1.0 ppm deviation).

EXAMPLE 7 A. 5-Alkoxypyrrolo[3,2-b]pyridines (Compound 7x)

To a stirred solution of potassium t-butoxide (12.34 g, 110 mmol, 2.2eq) in anhydrous dimethylformamide or tetrahydrofuran (referred to belowas the reaction medium) cooled at -10° C. under a nitrogen atmospherewas added dropwise a solution of (4-chlorophenoxy)acetonitrile (9.22 g,55mmol, 1.1 eq) and 2-alkoxy-5-nitropyridine (50 mmol) in anhydrousdimethylformamide or tetrahydrofuran (All 2-alkoxy-5-nitropyridines wereprepared using the methodology of H. L. Friedman, et al., J. Am. Chem.Soc., 69, 1204 (1947), with minor modifications in reaction times,temperatures and methods of purification). The resulting deep purplereaction solution was then maintained at -10° C. under nitrogen for1hour. Aqueous hydrochloric acid was added (80 mL, 5% HCl), and theresulting mixture was allowed to warm to room temperature. The reactionmixture was extracted with methylene chloride (3×50 mL), and theseextracts were combined, dried (MgSO₄), and evaporated under reducedpressure. The residual oil was passed through a silica gel filter(approximately 200 g) followed by methylene chloride/hexanes (1:1, 2L).This filtrate was evaporated under reduced pressure, and the residualoil (containing the desired (6-alkoxy-3-nitro-2-pyridyl)-acetonitrile)was dissolved in acetic acetic and 10% palladium/carbon was added (10%by weight of oil). This mixture was hydrogenated under 3 atm hydrogenfor 6 hours. The resulting mixture was filtered through diatomaceousearth (Celite (trademark)), and the filtrate was evaporated underreduced pressure. The residual oil was placed in water (50mL), and thepH was adjusted to 10 with addition of sodium carbonate. This mixturewas extracted with methylene chloride (2×100 mL), and these extractswere combined, dried (MgSO₄), and evaporated under reduced pressure.Chromatography using silica gel (approximately 200 g) and elution withtheappropriate solvent system yielded the desired5-alkoxypyrrolo[3,2-b]pyridine (Compound 7x). The compounds prepared aredescribed more specifically below.

B. 5-Ethoxypyrrolo[3,2-b]pyridine (Compound 7b)

The reaction solvent was tetrahydrofuran. Elution first with methylenechloride and then with methylene chloride/ethyl ether (9:1) yieldedCompound 7b (19%) as a yellow solid: mp, 156°-157.5° C.; IR (KBr) 1620,1570, 1485, 1470, 1445, 1410, 1390, 1365, 1340, 1305 cm⁻¹; ¹ H NMR(CDCl₃) δ 8.35 (br s, 1H), 7.55 (d, J =8.5 Hz, 1H), 7.28 (t, J =3.2 Hz,1H), 6.58 (d, J =9.0 Hz, 1H), 6.57-6.55 (m, 1H), 4.41 (q, J =7.0 Hz,2H), 1.40 (t, J=7.1 Hz, 3H); LRMS (m/z, relative intensity) 163 (32),162 (M+, 89), 147 (100), 134 (85), 119 (22), 118 (75), 117 (31), 106 (83), 105 (48), 79 (49); Anal. calcd. for C₉ H₁₀ N₂ O: C, 66.65; H, 6.21;N, 17.27; found: C, 66.31; H, 6.18;N, 17.15.

C. 5-Propoxypyrrolo[3,2-b]pyridine (Compound 7c)

The reaction solvent was tetrahydrofuran. Elution first with methylenechloride and then with 1% methanol in methylene chloride yieldedCompound 7c (23%) as a yellow solid: mp, 114°-116° C.; IR (KBr)1615,1610, 1585, 1475, 1410, 1380, 1305 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8. 1(br s, 1H), 7.57 (d, J =8.7 Hz, 1H), 7.31-7.29 (m, 1H), 6.60 (d, J=8.9Hz, 1H), 6.59-6.57 (m, 1H), 4.31 (t, J= 6.8 Hz, 2H), 1.88-1.76 (m, 2H),1.04 (t, J =7.4 Hz, 3H); ¹³ C NMR (CDCl₃) δ 158.8, 142.4, 127.6, 124.2,122.3, 104.6, 100.9, 66.4, 22.1, 10.6; Anal. calcd. for C₁₀ H₁₂ N₂ O: C,68.16; H, 6.86; N, 15.90,; found: C, 67 56; H, 6.43; N, a15.71.

D. 5-Isopropoxypyrrolo[3,2-b]pyridine (Compound 7d)

The reaction solvent was tetrahydrofuran. Elution first withether/hexanes (1:2, 4000 mL) and then with ether/hexanes (1:1) yieldedCompound 7d (16% from isolated(6-isopropoxy-3-nitro-2-pyridyl)acetonitrile) as an off-white solid: mp,104.5-107.5°; IR (KBr) 1620, 1575, 1480, 1455,1410, 1390, 1335, 1310cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.77 (br m, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.28(t, J=2.9 Hz, 1H), 6.54 (d, J=8.4Hz, 1H), 6.52 (br m, 1H), 5.38 (sept,J=6.3 Hz, 1H), 1.35 (d, J=6.3 Hz, 6H); ¹³ C NMR (CDCl₃) δ 159.4, 142.8,126.6, 124.3, 122.0,106.5, 102.4, 67.7, 22.2; LRMS (m/z, relativeintensity) 177 (7), 176 (M+, 51), 161 (30), 134 (100), 106 (57), 79(20). Anal. calc'd for C₁₀ H₁₂ N₂ O: C, 68.16; H, 6.86; N, 15.90; found:C, 67.95; H, 6.77;N, 15.81.

E. 5-Butoxypyrrolo[3,2-b]pyridine (7e)

The reaction solvent was tetrahydrofuran. Elution with a 1-3% methanolgradient in methylene chloride yielded Compound 7e (36%) as an off-whitesolid: mp, 92-93° C.; IR (KBr) 2960-2750, 1620, 1570, 1490, 1460, 1415,1395, 1340, 1320 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.5 (br s, 1H), 7.56 (d, J=8.9Hz, 1H), 7.30 (t, J=3.0 Hz, 1H), 6.60 (d, J=8.8Hz, 1H), 6.57 (m, 1H),4.35 (t, J=6.7 Hz, 2H), 1.82-1.72 (m, 2H), 1.55-1.42(m, 2H), 0.96(t,J=7.4 Hz, 3H); ¹³ C NMR (CDCl₃) δ 160.1, 142.5, 126.4, 124.1, 121.8,106.0, 102.7, 65.7, 31.4, 19.4, 14.0; LRMS (relative intensity) 191(26), 190 (67, M+), 160 (35), 147 (52), 135 (25),134 (100), 118 (21),117 (32), 106 (60), 105 (28), 78 (19); Anal. calc'd for C₁₁ H₁₄ N₂ O: C,69.45; H, 7.42; N, 14.72; found C, 69.20; H, 7.33; N, 14.58.

F. 5-t-Butoxypyrrolo[3,2-b]pyridine (Compound 7f)

The reaction solvent was tetrahydrofuran. Elution first with methylenechloride and then with 1% methanol in methylene chloride yielded amixture, which was re-chromatographed using silica gel (approximately100 g) and elution with ethyl ether/hexanes (1:1) to afford Compound 7f(15%) as an off-white solid: mp, 109°-110° C.; IR (KBr) 1615, 1570,1470, 1450, 1410, 1390, 1365, 1300 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.1 (br s,1H), 7.52 (d, J=8.8 Hz, 1H), 7.29-7.27 (m,1H), 6.56 (d, J=8.5 Hz, 1H),6.55-6.53 (m, 1H), 1.57 (s, 9H); ¹³ C NMR(CDCl₃) δ 159.1, 143.1, 126.6,124.6, 121.1, 109.4, 103.0, 79.2,29.0; LRMS (m/z, relative intensity)190 (M+, 17), 135 (31), 134 (100), 106(57), 105 (22 ), 79 (22),; Anal.calcd. for C₁₁ H₁₄ N₂ O: C,69.45; H, 7.42; N, 14.72; found: C, 69.37; H,7.48; N, 14.49.

G. 5-Benzyloxypyrrolo[3,2-b]pyridine (Compound 7g)

The reaction solvent was dimethylformamide. Raney nickel (washed withethanol) was used in place of palladium on carbon. Elution withmethylene chloride yielded Compound 7g (27% from isolated(6-benzyloxy-3-nitro-2-pyridyl)acetonitrile) as an off-white solid: mp,146.0-148.0° C.; IR (KBr) 1605, 1580, 1500, 1470, 1450, 1410, 1300 cm⁻¹; ¹ H NMR (CDCl₃) δ 8.47 (br m, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.50-7.48(m, 2H), 7.39-7.27 (m, 4 H), 6.67 (d, J=8.4 Hz, 1H), 6.60-6.58 (m, 1H),5.45 (s, 2H); ¹³ C NMR (CDCl₃) δ 159.7, 142.6, 137.8, 128.4, 128.0,127.7, 126.7, 124.5, 122.1, 106.0, 102.6, 67.7; LRMS (M/z, relativeintensity) 225 (38), 224 (M+, 89), 223 (40), 207 (20), 147 (61), 119(31), 118 (75), 105 (30), 92 (22), 91 (100),65 (36). Anal. calc'd forC₁₄ H₁₂ N.sub. 2 O: C, 74.98; H, 5.39; N, 12.49; found: C, 74.80; H,5.22; N, 12.42.

H. 5-Cyclopentoxvpyrrolo[3,2-b]pyridine (Compound 7h)

The reaction solvent was tetrahydrofuran. Elution with 2.5% methanol inmethylene chloride yielded a mixture which was triturated in ethylether, and the undissolved solid was filtered to yield Compound 7h (29%)as a white solid; mp, 99°-101° C.; IR (KBr) 1610, 1580, 1480, 1445,1510, 1360, 1320, 1300 cm⁻¹ ; ¹ H NMR (CDCl₃) 8.1 (brs, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.29 (t, J=2.9 Hz, 1H), 6.58-6.56 (m, 1H),6.55 (d, J =8.7Hz, 1H) 5.52-5.47 (m, 1H), 2.05-1.92 (m, 2H), 1.88-1.75 (m,4H),1.70-1.55 (m, 2H); LRMS (m/z, relative intensity) 203 (30, 202 (M+, 62),174 (11), 159 (15), 135 (40), 134 (100 ), 133 (20), 117 (28), 106 (64),105 (35), 79 (38); Anal. calc'd for C₁₄ H₁₂ N₂ O[0.25H₂ O]: C, 69.71; H,7.07; N, 13.54; found: C, 69.81; H, 6.66; N, 12.30.

EXAMPLE 8 5-Hydroxypyrrolo[3,4-b]pyridine (Compound 7i)

A mixture of 5-benzyloxypyrrolo[3,4-b]pyridine (Compound 7f, 1.38 g,6.15 mmol), 5% Pd/C (0.30 g), and absolute ethanol (25 mL) was shakenunder a hydrogen atmosphere (3 atm) for 30 minutes. The resultingmixture was filtered through diatomaceous earth (Celite (trademark)),and the filtratewas evaporated under reduced pressure. The residualsolid was triturated inethyl ether to yield Compound 7i (0.80 g, 5.96mmol, 97%) as an off-white crystalline solid: mp, 280.0°-282.0° C.: IR(KBr) 1640, 1615, 1605, 1455, 1430, 1400, 1380, 1365 cm⁻¹ ; ¹ H NMR(DMSO-d₆) δ 11.4 (br m, 2H), 7.56 (d, J=9.7 Hz, 1H), 7.16 (d, J=3.1 Hz,1H), 6.01-5.93 (m, 2H); ¹³ C NMR (DMSO-d₆) 162.0, 131.9, 127.9, 125.0,118.2, 112.2, 94.5; LRMS (m/z, relative intensity) 135 (41), 134 (M+,100), 106 (66), 105 (42), 79 (59), 53 (31), 52 (52). Anal. calcd. for C₇H₆ N₂ O: C, 62.68; H, 4.51; N, 20.88; found: C, 62.40; H, 4.40; N,20.76.

EXAMPLE 9 5-Dimethylaminopyrrolo[3,2-b]pyridine (Compound 7j)

A mixture of (6-dimethylamino-3-nitro-2-pyridyl)-acetonitrile (Compound5c,2.06 g, 10.0 mmol), Raney nickel (0.70 g, washed thoroughly withabsolute ethanol), and absolute ethanol/acetic acid (4:1, 50 mL) wasshaken under ahydrogen atmosphere (3 atm) for 3 hours. The resultingmixture was filteredthrough diatomaceous earth (Celite (trademark)), andthe filtrate was evaporated under reduced pressure. The residual oil wasdissolved in water(25 mL), the pH was adjusted to 10 with sodiumcarbonate, and the mixture was extracted with methylene chloride (3×25mL). These extracts werecombined, dried (MgSO₄), and evaporated underreduced pressure to yield an oil. This oil was dissolved in ethylacetate (10 mL), and this solution was passed through an alumina (basic)filter (approximately 100 g) followed by ethyl acetate (1500 mL). Theresulting filtrate was evaporated under reduced pressure to yieldCompound 7j (0.44 g, 2.73 mmol,27%) as a white solid: mp, 149.0°-151.0°C.; IR

(KBr) 1620, 1590, 1505, 1475, 1455, 1410 cm⁻¹ ; ¹ H NMR (CDCl₃) 8.68 (brm, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.21 (t, J=3.0 Hz, 1H), 6.50 (d, J=8.8Hz, 1H), 6.49-6.47 (m, 1H), 3.10 (s, 6H); ¹³ C NMR (CDCl₃) δ 156.6,144.3, 126.4, 120.8, 102.7, 102.0, 39.3; LRMS (m/z, relative intensity)162 (21), 161 (M+, 99), 160 (23), 146 (80),132 (100), 119 (36), 118(82), 117 (81), 90 (19). Anal. Calcd. for C₉ H₁₁ N₃ : C, 67.06; H, 6.88;N, 26.08; found: C, 66.69; H, 6.81; N, 25.94.

EXAMPLE 10 5-Methylpyrrolo[ 3,2-b]pyridine (Compound 7k)

To a stirred slurry of sodium hydride (60%) in oil, 18.2 g, 455 mmol,2.0 eq) in anhydrous tetrahydrofuran (250 mL) under nitrogen at 0° C.was added dropwise a solution of di-t-butylmalonate (97.9 g, 453 mmol,2.0eq) in anhydrous tetrahydrofuran (150 mL). The mixture was allowed towarm to room temperature, and was then heated at 45° C. for 30 minutes.The reaction mixture was then cooled to room temperature and2-chloro-t-nitropyridine (35.9 g, 226 mmol) was added as a solid all atonce. The resulting mixture was heated at reflux (66° C.) under nitrogenfor 2 hours. The reaction was then cooled, placed in separatory funnel,water (200 mL) was added, the pH was adjusted to 6 with 10% HCl, ethylether (200 mL) was added, and the organic layer was removed. Theremaining aqueous layer was then extracted once with ethyl ether (200mL),and the organic extracts were combined, dried (MgSO₄), andevaporated under reduced pressure. The resulting solid/oil mixture wasstirred in ethyl ether/hexanes (1:1, 300 mL) and the undissolved solidwas filtered to yield t-butyl (2-t-butoxycarbonyl)-(5-nitro-2-pyridyl)acetate (46.0 g,135 mmol, 60%) as a white, crystalline solid: mp,105°-106° C.; IR (KBr) 1740, 1730, 1600, 1575, 1520, 1460, 1390, 1370,1365, 1330, 1310 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 9.36 (d, J=2.6 Hz, 1H),8.48(dd, J=2.6 and 8.7 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 4.89 (s, 1H),1.47(s, 18H); LRMS (m/z, relative intensity) 227 (11), 209 (49), 182(52), 164 (33), 57 (100); Anal. calc'd for C₁₆ H₂₂ N₂ O₆ : C, 56.80; H,6.55; N, 8.28; found: C, 56.72; H, 6.57; N, 8.14.

To a stirred solution of potassium t-butoxide (11.0 g, 97.6 mmol, 3.3eq) in anhydrous tetrahydrofuran (100 mL) at -10° C. under nitrogenwasadded dropwise a solution of (4-chlorophenoxy)acetonitrile (5.45 g,32.5 mmol, 1.1 eq) and t-butyl(2-t-butoxycarbonyl)-(5-nitro-2-pyridyl)acetate (10.0 g, 29.6 mmol) inanhydrous tetrahydrofuran (75 mL). The resulting deep purple coloredreaction was stirred at room temperature under nitrogen for 64 hours. 5%HCl (72 mL) was added to the reaction solution, and the resultingaqueous mixture was extracted with ethyl acetate (3×200 mL). Theseextracts were combined, dried (MgSO₄), and evaporated under reducedpressure to yield an oil. Column chromatography of this oil using silicagel (approximately 300 g) and elution with an ethyl ether/hexanesgradient (10-40% ethyl ether in hexanes) afforded(3-nitro-6-(dicarbo-t-butoxymethyl)-2-pyridyl)acetonitrile (5.14 g, 13.6mmol, 46%) as a clear, pale yellow oil; IR (CHC 13) 3670, 2970, 2925,2255, 1725, 1600, 1580, 1520, 1450, 1395, 1370, 1350, 1320 cm⁻¹ ; ¹ HNMR (CDCl₃) δ 8.49 (d, J=8.6 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 4.92 (s,1H), 4.40 (s, 2H), 1.48 (s, 18H); ¹³ C NMR (CDCl₃) δ 165.4, 158.8,145.0, 143.4, 133.9, 125.0, 115.1, 83.5, 62.3, 27.9, 26.8; LRMS (M/z,relative intensity) 322 (3), 265 (19), 248 (24), 221 (75), 204 (23),203, (47), 57 (100); HRMS calcd. for C₁₈ H₂₄ N₃ O₆ ([M+]+H): 378.1665,found: 378.1637; Anal. calc'd for C18H C, 57.29; H, 6.14; N, 11.13;found: C, 56.96; H, 6.10; N, 10.97.

A mixture of (3-nitro-6-(dicarbo-t-butoxymethyl)-2-pyridyl)acetonitrile(6.85 g, 18.2 mmol), dioxane (150 mL), and 2M sulfuric acid (25 mL) washeated at reflux for 12 hours. The resulting solution was cooled,neutralized with sodium carbonate, and extracted with ethyl acetate(3×50 mL). These extracts were combined, dried (MgSO₄), and evaporatedunder reduced pressure to yield an oil. This oil was passed through asilica gel filter (approximately 100 g) followed by methylene chloride.This filtrate was evaporated under reduced pressure to afford(6-methyl-3-nitro-2-pyridyl)acetonitrile (1.91 g, 10.8 mmol, 59%) as anoff-white solid: mp, 70°-72° C.; IR (KBr)

2245, 1595, 1580, 1515, 1450, 1370, 1340 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.38(d, J=8.4 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 4.39 (s, 2H), 2.70 (s, 3H);¹³ C NMR (CDCl₃) δ 164.7, 145.3, 142.1, 133.8, 123.9, 115.1, 27.1, 24.7;LRMS (m/z, relative intensity) 178(29), 177 (M+, 93), 60 (16), 132 (26),131 (92), 105 (37), 104 (100), 92 (32), 79 (50), 78 (51), 77 (81), 63(54); HRMS 3.98; N, 3.72; found: C, 53.90; H, 3.95; N, 23.47.

A mixture of (6-methyl-3-nitro-2-pyridyl)-acetonitrile (1.83 g, 10.3mmol),Raney nickel (0.20 g) and acetic acid/ethanol (3:7) was shakenunder an atmosphere of hydrogen for 4 hours. The resulting mixture wasfiltered, and the filtrate was evaporated under reduced pressure. Theresidual oil was partitioned between saturated sodium hydrogen carbonate(25 mL) and ethyl acetate (25 mL). The organic layer was removed, andthe aqueous layer was extracted with ethyl acetate (2×25 mL). Theorganic extracts were combined, dried (MgSO₄), and evaporated underreduced pressure to yield a yellow solid. Column chromatography of thissolid using silica gel (approx 50 g) and elution with 5% methanol inmethylene chloride yielded Compound 7k (0.32 g, 2.4 mmol, 24%) as a tansolid: mp, 200°-202° C.; IR (KBr) 1610, 1570, 1465, 1445, 1405, 1290cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 11.15 (br s, 1H), 7.65 (d,J=8.5 Hz, 1H), 7.54(m, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.45 (br m, 1H), 2.51 (s, 3H); .sup. 13C NMR (DMSO-d₆) 50.0, 145.7, 128.5, 126.6, 118.7, 116.0, 101.1, 24.2;Anal. calc'd for C₈ H₈ N₂ ; C, 72.70; H, 6:10; N, 21.20; found: C,72.22; H, 6.19; N, 21.25.

EXAMPLE 11 5-Chloropyrrolo[2,3-c]pyrridine (Compound 8)

A mixture of 200 mg Raney nickel (washed thoroughly with absoluteethanol),Compound 6 (2.35 g, 11.89 mmol), and 1:1 absoluteethanol/acetic acid (50 ml) was shaken under a hydrogen atmosphere (3atm) for 2 hours. The reaction mixture was filtered, and the filtratewas evaporated under reduced pressure. The residual oil was placed in asaturated solution of sodium bicarbonate (25 ml), and this aqueousmixture was extracted with methylene chloride (3×25 ml). These extractswere combined, dried (MgSO₄), and evaporated under reduced pressure. Theresidual solid was stirred in cold anhydrous ether, and the undissolvedsolid was filtered to yield Compound 8 (0.80 g, 5.24 mmol, 44%) as awhite crystalline solid: mp. 192°-194° C.; IR (KBr) 3400, 3080-2750,1610, 1565, 1495, 1455, 1290 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 9.55 (br s, 1H),8.59 (s, 1H), 7.56 (s, 1H), 7.48 (t,J=2.8 Hz, 1H), 6.53-6.51 (m, 1H); ¹³C NMR (DMSO-d₆) δ 138.8, 135.4, 133.6, 132.6, 132.0, 113.8, 100.5; LRMS(m/z, relative intensity) 154 (34), 153 (13), 152 (M+, 100), 117 (68),90 (19), 63 (14); HRMS calculated for C₇ H₅ ClN₂ : 152.0141, found:152.0136.

EXAMPLE 12 5-Methoxypyrrolo[2,3-c]pyridine (Compound 9)

A mixture of 4-methyl-5-nitro-1H-pyridine-2-one (5.00 g, 32.44 mmol),thionyl chloride (20 ml), and two drops of dimethylformamide was heatedatreflux under nitrogen for 52 hours. The resultant orange coloredsolution was evaporated under reduced pressure, and a small amount ofanhydrous toluene was added and then removed via evaporation underreduced pressure to remove traces of thionyl chloride. The residual oilthen passed througha silica gel filter (dried at 150° C. under vacuumovernight, approximately 100 g) followed by methylene chloride (1 1).This filtrate was evaporated under reduced pressure to afford2-chloro-4-methyl-5-nitropyridine (5.30 g, 30.71 mmol, 95%) as an orangeoil, which crystallized below 0° C.; IR (CHCl₃) 1605, 1550, 1520, 1450,1360, 1345 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 9.03 (s, 1H), 7.83 (s, 1H), 2.60 (s,3H); LRMS (m/z, relative intensity) 174 (25), 173 (19), 172 (M+, 68),157 (74), 155 (100), 128 (27), 101 (47), 100(55], 99 (74), 90 (43), 75(36).

To a stirred solution of sodium (2.30 g, 100mmol, 3.8 eq) in absolutemethanol (75 ml) at 0° C., a solution of2-chloro-4-methyl-5-nitropyridine (4.50 g, 26.07 mmol) in absolutemethanol (15 ml) was added dropwise rapidly. The resulting dark coloredsolution was stirred at room temperature for 30 minutes, and then it wasconcentrated to a solid via evaporation under reduced pressure. Thissolidwas placed in water (25 ml), the pH of which was adjusted to 6 withconcentrated HCl, and this aqueous mixture was extracted with ethylacetate (2×25 ml). These extracts were combined, dried (MgSO₄),andevaporated under reduced pressure to yield2-methoxy-4-methyl-5-nitropyridine (4.30 g, 25.57 mmol, 98%) as anorange solid: mp, 70°-72° C.; ¹ H NMR (DMSO-d₆) δ 8.94 (s, 1H), 6.97 (s,1H), 3.99 (s, 3H), 2.58 (s, 3H); LRMS (m/z relativeintensity) 168 (M+,98), 167 (100), 151 (34), 138 (24), 80 (17).

A solution of 2-methoxy-4-methyl-5-nitropyridine (4.30 g, 25.57 mmol)and dimethylformamide dimethylacetal (35 ml) was heated at reflux undernitrogen for 40 hours. Ethyl acetate was added to this solution (150ml), and this mixture was washed with water (150 ml). The aqueousextract was back-extracted with ethyl acetate (100 ml), and the organicextracts were combined, dried (Na₂ O₄), and evaporated under reducedpressure to yield a purple solid. The solid was dissolved in absoluteethanol (200 ml), and 5% palladium on carbon (3.0 g) was added to thissolution which was shaken under a hydrogen atmosphere (3 atm) for 3hours. The resultant reaction mixture was filtered, and the filtrate wasevaporated under reduced pressure. Flash chromatography of the residueyielded compound 9 (2.05 g, 13.84 mmol, 54% last step, 50% overall) as awhite crystalline solid: mp, 123°-124° C.; IR (KBr) 1625, 1580, 1490,1460, 1320, 1150 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 11.28 (br s, 1H), 8.37 (s,1H), 7.57 (t, J=2.8 Hz, 1H), 6.86 (s, 1H), 6.33 (br m, 1H), 3.82 (s,3H); ¹³ C NMR (DMSO-d₆) δ 157.2, 136.4, 131.5, 130.7, 130.0, 99.6, 96.8,53.4; LRMS (m/z, relative intensity) 149 (20), 148 (M+, 98), 147 (100),119 (46), 118 (79), 117 (26), 105 (31), 91 (15), 70 (16); HRMScalculated for C₈ H₈ N₂ O:148.0657, found: 148.0613.

EXAMPLE 13

Male CD-1 mice (17-19 g at arrival) which had acclimated to the animalfacility for approximately 6 days were housed 8 to a box. The mice wereweighed and control or a compound of the present invention (drug) wasthenadministered morning and afternoon for two days with at least sixhours between sessions. On the third morning, the animals were weighed.Each of compounds 1a-1m, 2 and 3a-3c demonstrated at least a 5 percentreduction in body weight (as compared to day 1 morning weight) of druganimals versus control animals at a dosage of 32 mg/kg.

I claim:
 1. A compound of the formula ##STR5## wherein one of A, B, Dand E is N and the remaining three atoms are C; R¹ and R² areindependently selected from hydrogen and C₁ to C₆ alkyl; and R³, R⁴, R⁵and R⁶ are independently selected from hydrogen, halogen, hydroxy, C₁-C₆ alkyl, C₁ -C₈ alkoxy, phenyl-C₁ -C₆ alkoxy, phenoxy, --NR⁷ R⁸wherein R⁷ and are independently selected from hydrogen, C₁ -C₆ alkyl,C₁ -C₆ alkanoyl, and COOR⁹ wherein R⁹ is hydrogen or C₁ -C₆ alkyl,cyano, COOR¹⁰ wherein R¹⁰ is hydrogen or C₁ -C₆ alkyl, and CONR¹¹ R¹²where R¹⁰ and R¹¹ are independently selected from hydrogen and C₁ -C₆alkyl and the pharmaceutically acceptable salts thereof.
 2. A compoundaccording to claim 1, wherein R¹, R², R⁵ and R⁶ are hydrogen, R³ isabsent, R⁴ is as defined in claim 1, A is N, and B, D and E are C.
 3. Acompound according to claim 2, wherein R⁴ is hydrogen, methoxy, ethoxy,propoxy, butoxy or hydroxy.
 4. A pharmaceutical composition for treatingobesity, depression or disorders wherein aggression is a symptom,comprising an anti-obesity, anti-depressant or anti-aggressive effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 5. A composition to claim 4, wherein R¹, R², R⁵ andR⁶ are hydrogen, R³ is absent, R⁴ is as defined in claim 1, A is N, andB, D and E are C.
 6. A composition according to claim 5, wherein R⁴ ishydrogen, methoxy, ethoxy, propoxy, butoxy or hydroxy.
 7. A method oftreating or preventing obesity, depression or disorders whereinaggression is a symptom in mammals comprising administering to a mammalin need of such treatment an anti-obesity, anti-depressant oranti-aggressive effective amount of a compound according to claim
 1. 8.A method according to claim 7, wherein R¹, R², R⁵ and R⁶ are hydrogen,R³ is absent, R⁴ is as defined in claim 7, A is N, and B, D and E are C.9. A method according to claim 8 wherein R⁴ is hydrogen, methoxy,ethoxy, propoxy, butoxy or hydroxy.